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British Journal of Anaesthesia 107 (S1): i27i40 (2011)



Multimodal therapies for postoperative nausea and vomiting,

and pain
A. Chandrakantan* and P. S. A. Glass
Department of Anesthesiology, Stony Brook University Medical Center, Stony Brook, NY, USA
* Corresponding author. E-mail: arvind.chandrakantan@stonybrook.edu

Editors key points

Multimodal approaches to both

PONV and pain have been shown
to improve treatment efficacy
and reduce side-effects for
high-risk patients undergoing
surgical procedures.
These approaches integrate
both pharmacological and
interventions made before
operation, intraoperatively, and
after operation.

Keywords: nausea, postoperative; pain, postoperative; vomiting, postoperative

Postoperative nausea and vomiting

While multiple advances have been made in the last several
years in minimizing adverse outcomes after anaesthesia,
patients continue to rank nausea/vomiting as their most undesirable surgical outcome.1 2 While the incidence of postoperative nausea and vomiting (PONV) varies considerably
in both the inpatient and outpatient setting,3 6 studies indicate that the incidence of nausea ranges from 22% to 38%7
and the incidence of vomiting ranges from 12% to 26%.7
Multiple risk factors have been identified that increase the
incidence of PONV. The incidence of PONV in high-risk
patients is much higher (60 70%).8 The administration of
antiemetic drugs reduces this incidence, especially the judicious use of multiple antiemetics.9 Post-discharge nausea
and vomiting (PDNV) defined from 24 h post-discharge up
to 72 h has an incidence of up to 55%.5 10 12 It appears
that the risk factors for PDNV are different from those for
The multimodal approach of using more than one antiemetic was initially conceived and described due to the
limited effects of single-drug therapy14 and the finding that

multiple drug therapies resulted in a lower incidence of

PONV.15 While numerous trials have validated the utility of
this methodology, it should be understood that the multimodal approach extends far beyond intraoperative pharmacotherapy and starts with non-pharmacological interventions in
the preoperative area.16

Identification of risk factors for PONV

Several factors such as female gender and history of
PONV/motion sickness were identified retrospectively as
early as 196017 as risk factors for PONV. In 1993, a
study was performed using logistic regression analysis to
prospectively look at factors for PONV in a small cohort
of patients.18 Subsequently, Apfel and colleagues8 identified four risk factors that form the basis for the Apfel
scoring system: female gender, history of PONV/motion
sickness, non-smoking status, and use of postoperative
opioids. Each risk factor increases the likelihood of PONV
by 18 22%.8 Identification of baseline risk using the
Apfel criteria is important, since an increase in risk

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Postoperative nausea and

vomiting along with pain are
among the major perioperative
concerns of most surgical
patients and their anaesthetists.

Summary. Postoperative nausea and vomiting (PONV) and pain are two of the major
concerns for patients presenting for surgery. The causes of PONV are multifactorial
and can largely be categorized as patient risk factors, anaesthetic technique, and
surgical procedure. Antiemetics work on several different receptor sites to prevent
or treat PONV. This is probably why numerous studies have now demonstrated
that using more than one antiemetic is usually more effective and results in fewer
side-effects than simply increasing the dose of a single antiemetic. A multimodal
approach to PONV should not be limited to drug therapy alone but should involve
a holistic approach starting before operation and continuing intraoperatively with
risk reduction strategies to which are added prophylactic antiemetics according to
the assessed patient risk for PONV. With the increasing understanding of the
pathophysiology of acute pain, especially the occurrence of peripheral and central
hypersensitization, it is unlikely that a single drug or intervention is sufficiently
broad in its action to be adequately effective, especially with moderate or greater
pain. Although morphine and its congeners are usually the foundation of pain
management regimens, as their dose increases so does the incidence of sideeffects. Thus, the approach for the management of acute postoperative pain is to
use multiple drugs or modalities (e.g. regional anaesthesia) to maximize pain
relief and reduce side-effects.


Pathophysiology of PONV
Emesis is believed to be governed by the emesis centre in the
brain, which receives several afferent inputs (Fig. 1). Vagal
input from the gut can activate the emetic centre, and also
afferent action from the chemoreceptor trigger zone (CTZ).
The CTZ sits outside the blood brain barrier and contains
several different receptors that modulate its activity. Most
antiemetic medications act by either a direct or indirect
antagonizing of emetogenic substances on receptors in
the CTZ.
As there are several receptor systems involved in the development and treatment of PONV, it seems obvious that a
combination of drugs acting at the different receptors
would have greater efficacy than a single drug. Increasing
the dose of a single class of drug does not necessarily decrease the incidence of PONV, especially in patients with
risk factors.32 33 Also, the incidence of side-effects increases
as the dose increases in many drug classes (Table 1).34 The
multimodal technique therefore offers the benefits of
enhanced PONV reduction with a lower incidence of
Intuitively, the combined effects of drugs should be synergistic since each antiemetic intervention has a different
mode of action. However, current data for the agents available indicate that the effects are simply additive.9 35 36 This
observation underscores the importance of risk-stratifying
patients as noted above and a holistic approach emphasizing both pharmacological and non-pharmacological


Approach to multimodal therapy

Broadly, the multimodal approach constitutes both pharmacological and non-pharmacological therapies, which commences in the preoperative area and continues until
discharge of the patient. In the preoperative area, minimizing
anxiety is important. Anxiolysis with benzodiazepines has
been shown to reduce PONV in several small studies.37 38
Other interventions to minimize anxiety include optimizing information provided to the patient, a patient-friendly facility
layout, and positive and compassionate interactions with
staff. All of these interventions help minimize anxiety and
likely reduce the incidence of PONV due to its impact on PONV.
Preoperative dexamethasone reduces the incidence of
PONV.39 Aprepitant (a neurokinin-1 antagonist) administered
before anaesthesia is effective in reducing both vomiting and
nausea for up to 48 h after surgery.40 41 Pre-hydration with
oral carbohydrate containing clear fluids up to 2 h before
surgery also reduces PONV.42 Similarly, adequate i.v. fluid resuscitation has become part of the multimodal regimen43 44
with both crystalloids and colloids reducing PONV.45 The
choice of the type of fluid does not alter the incidence of
PONV significantly.46
The intraoperative approach starts with minimizing
factors that can increase PONV. Thus, the choice of anaesthetic is important. Inhalation anaesthetics, including
nitrous oxide (dose-dependent), are associated with an
increased risk of PONV. The use of regional anaesthesia
decreases the incidence of PONV compared with general anaesthesia.47 Although it would be ideal for patients at high
risk for PONV/PDNV, regional anaesthesia is not always available as an option. Total i.v. anaesthesia (TIVA) decreases the
incidence of PONV compared with inhalation anaesthetics
and N2O.43 More specifically, the use of propofol as both an
induction and maintenance agent (as TIVA) decreases the incidence of PONV,6 48 but might be associated with higher
cost.6 Propofol has direct antiemetic effects and has been
used after operation to treat PONV at doses of 1020 mg.
The minimum effective concentration of propofol for PONV
is 300 ng ml21.49 As patients usually wake up at propofol
concentrations of 1000 2000 ng ml21, the antiemetic
effect of propofol administered intraoperatively lasts for up
to 30 min after operation.
Analgesia is a key component of intraoperative anaesthesia, with opioids as the mainstay of treatment. However,
increasing intraoperative and postoperative opioid administration is associated with a much higher risk of PONV.28
Short-acting opioids do not increase the incidence of
PONV50 when used as part of a TIVA regimen, but do not
offer postoperative analgesia. Pain itself increases PONV,
and thus the objective is to create the optimal balance
between opioid administration and pain relief. There are
several analgesic alternatives to opioids that have become
available for i.v. administration in the last few years. Reducing the amount of opioids administered while obtaining
good pain relief is the ultimate objective. Non-steroidal
anti-inflammatory drugs (NSAIDs) decrease PONV compared

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factors increases the number of subsequent therapies

Although Apfel defined the risk criteria with the largest
impact on PONV, multiple other risk factors have been identified. These can be broadly divided into three categories:
patient risk factors, anaesthetic technique, and surgical procedure. Patient risk factors include female gender from
puberty, non-smoking status, previous history of PONV/
motion sickness, and genetic predisposition.3 19 22 Anaesthetic technique includes the use of inhalation agents,
nitrous oxide, large-dose neostigmine, and intraoperative
and postoperative opioid use.9 19 23 28 Surgical factors
include longer duration of surgery and different types of surgeries.8 20 22 29 However, whether longer surgeries are directly causal is difficult to prove, since higher doses of opioids
and longer exposure to inhalation anaesthetics (MAC-hours)
are likely to occur and are known risk factors of PONV.9 20 Although risk factors are well defined for the population and
are used to plan antiemetic therapy for a given individual,
they unfortunately are not highly predictive.30
In children, there are fewer data than in adults regarding
risk factors. However, Eberhart and colleagues31 identified
four risk factors: duration of surgery .30 min, age .3 yr,
strabismus surgery, and history of postoperative vomiting in
a parent, sibling, or the patient.

Chandrakantan and Glass


Multimodal therapies for PONV and pain

The chemoreceptor trigger zone and emetic centre








Muscarinic Dopamine (D2) Substance P


Receptor site

Nitrogen mustard
Digoxin glycoside


Opioid, analgesics
Vestibular portion
of 8th nerve





GI tract distension
Higher centres (vision, taste)

Fig 1 CTZ and emetic centre. With permission from Watcha and White.73

Table 1 Side-effects of commonly used antiemetics by drug class

Drug class



Headache, diarrhoea, constipation,



Dizziness, diarrhoea, headaches, weakness


Dizziness, mood changes, nervousness


Confusion, drying of mucosal membranes,

sedation, urinary retention


Prolonged QT interval (at doses 0.1 mg

kg21), hypotension, tachycardia,
extra-pyramidal symptoms


Sedation, disorientation

with opioids in numerous studies.51 53 There are clear data

for the opioid-sparing effects of NSAIDs and consequent reduction in PONV.54 Small doses of i.v. ketamine also provide
opioid-sparing55 with a trend towards reducing PONV.56 The
opioid-sparing effects described above have a dual role of
both reducing the incidence of PONV and enhancing overall
pain management as described for multimodal analgesia
Reversal of neuromuscular block is required for many
types of surgeries. Although multiple authors23 have demonstrated that high-dose neostigmine increases the risk of
PONV, a recent meta-analysis suggests no increased risk

with neostigmine use.57 This issue remains unclear, and

more study is needed on this issue.
Intraoperative antiemetics form the cornerstone of antiemetic therapy16 (Fig. 2). Apfel and colleagues9 demonstrated that using one or more antiemetic therapies (up
to 4) decrease the incidence of nausea and vomiting
significantly (Fig. 3). This study showed that with each additionally administered antiemetic, the risk of PONV was
further reduced by 30% (the so-called rule of 1/3). This extremely large study provides the foundation demonstrating
the validity of the multimodal model.58 Numerous studies
have shown that two antiemetic therapies significantly decrease the incidence of PONV compared with single-drug
prophylaxis in high-risk surgical populations.59 60 Although
there are data demonstrating the efficacy of different antiemetic therapies, too much of a good thing can be counterproductive. Recent data suggest that aprepitant, when
added to three different antiemetics, might actually increase
the incidence of PONV.61 With a minimal cost and sideeffects of the majority of antiemetics available, a more
liberal approach than suggested by the Apfel criteria or the
SAMBA (Society for Ambulatory Anesthesiology) guidelines
has been proposed.62
Acustimulation at the P6 acupoint has been shown to be effective in preventing PONV.63 64 A meta-analysis of acustimulation in pregnant patients has shown similar efficacy.65 As part
of a multimodal regime, acustimulation provides a further 30%
reduction of PONV when combined with 4 mg ondansetron (i.e.
similar efficacy as a second antiemetic).66 There are smaller


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Chandrakantan and Glass

Adult risk factors

Patient related
History of PONV/motion sickness
Female gender

Children risk factors

Surgery >30 min
Postop opioids
Age >3 years
Emetogenic surgery
Strabismus surgery
(type and duration)
History of POV/relative to PONV



Patient preferences
Fear of PONV
Frequency of
PONV causing

Reducing baseline risks

Avoidance/minimization of:
Nitrous oxide
Volatile anesthetics
High-dose neostigmine
Post-op opioids

Level of risk
0 RF=10%
1 RF=10%20%
2 RF=30%40%
3 RF=50%60%
4 RF=70%80%

Patient risk

Pick 1 or 2 interventions for adults
Pick 2 interventions for children



or Haloperidol



2 interventions/
multi approach

Portfolio of
and treatment

Propofol in
(rescue only)



Treatment options
If prophylaxis fails or was not received: use antiemetic
from different class than prophylactic agent
Readminister only if >6 h after PACU: do not
readminister dexamethasone or scopolamine

Use droperidol in children only if other

therapy has failed and patient is being
admitted to hospital
Some of the drugs may not have been studied
or approved by the FDA for use in children.

Fig 2 Algorithm for management of PONV. SAMBA guidelines for PONV from Gan and colleagues16 with permission.

studies that demonstrate that acupuncture decreases PONV

over 24 h;67 however, data for PDNV are lacking.
PDNV is quite common after outpatient surgery.5 However,
risk factors for PDNV are likely to be quite different from those
of PONV.13 Thus, the antiemetics that are effective and the
impact of multimodal therapy are also likely to be quite different. In a meta-analysis of PDNV, ondansetron and dexamethasone were more effective than placebo. However,


droperidol did not seem effective for PDNV prophylaxis. In

the few combination studies reviewed in this article, a combination of two drugs was more effective than a single drug.
For example, the number needed to treat (NNT) with ondansetron 4 mg was 13, while for a combination of two antiemetics, the NNT was about 5. The authors concluded that
the routine use of two or more antiemetics for PDNV in highrisk patients is justified.11 The data on the efficacy of specific

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Wait and see


Multimodal therapies for PONV and pain

and N2O


and air

and N2O

and air

Incidence of postoperative
nausea and vomiting (%)


2 3
0 1 2
No. of antiemetics

Fig 3 Effect of multiple antiemetic therapies. With permission from Apfel and colleagues. & Massachusetts Medical Society.9

antiemetics and their combination are still lacking, so definitive conclusions are difficult to make at present.

A planned multimodal algorithm starting in the preoperative
area can significantly reduce the incidence of PONV. This
includes both a strategy for risk assessment, risk reduction,
and therapy targeted at matching the risk with the number
of antiemetics administered. Most patients present with at
least one Apfel criteria risk factor. As the cost both in
money and side-effects is small with present antiemetics,
the authors preference is to start with a minimum of two
antiemetics (generally dexamethasone 4 mg soon after induction and ondansetron 4 mg 20 min before the end of
surgery). To this are added additional antiemetics depending
on other risk factors. Unfortunately, the efficacy of the multimodal technique in preventing PDNV remains unclear. Although many of the same risk factors carry through to
discharge, it is uncertain whether a similar multimodal approach to PDNV is similarly effective.

Multimodal approach to pain management

Despite advancements in the understanding of the pathophysiology of pain and pharmacotherapeutics, pain remains
poorly treated in both the inpatient and ambulatory
setting.68 The importance of quantifying and treating acute
postoperative pain is not only because of how unpleasant it
is, but also because, if poorly treated, there is a risk for the
development of chronic pain and its incumbent morbidity.69
Besides concerns of prolonged recovery and rehabilitation,
pain still ranks among the highest patient and physician

concerns for undesirable surgical outcomes.1 2 The physiological consequences of pain can be quite deleterious to
the patient. The incidence of mild-to-moderate pain after a
variety of moderately invasive surgeries is about 6265%68
and the visual analogue scale remains .4 in about 10% of
patients 7 days after discharge.70 However, the incidence of
the progression to chronic pain varies by surgery.71 Today,
acute postoperative pain is recognized to have two components, an earlier inflammatory component and a later neuropathic component. Just alleviating the inflammatory
component in susceptible patients might not be sufficient;
addressing the neuropathic pain component can be equally
important in the prevention of chronic pain.72
Similar to the multimodal approach to PONV, the multimodal approach to pain management was conceived due
to limitations in single-drug therapy, namely opioids and
NSAIDs,73 74 for which there is an increasing incidence of
side-effects with increasing doses. Kehlet and Dahl75 were
the first to suggest that combining medications acting
through different mechanisms lowers doses of analgesics,
pain is better controlled, and there is a lower incidence of
side-effects. This has since been demonstrated in multiple
studies.76 80 Again similar to PONV, the multimodal approach to pain management starts in the preoperative area.

Identification of risk factors for pain

Unlike PONV with the Apfel criteria, clearly quantifiable risk
factors for postoperative pain have not been identified.
While qualitative risk factors do exist, basing analgesic
therapy on the number of risk factors is not feasible.
However, identification of risk factors and assessment is


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Pathophysiology of pain
Although there are multiple definitions of pain, most experts
agree that it is primarily a sensory experience.72 There are
two major components that contribute to perioperative
pain, namely inflammatory and neuropathic pain. Both of
these states share multiple common features and can be
experienced either jointly or separately.93
A nociceptive stimulus from any source, whether thermal,
mechanical, or otherwise, causes a release of multiple inflammatory substances in the affected tissue (Fig. 4). This
leads to sensitization of nerves that supply the affected
area, a phenomenon known as peripheral sensitization.
Owing to afferent input to the central nervous system
(CNS), the CNS also becomes sensitized, a phenomenon
known as central sensitization. Both forms of sensitization
are mediated through numerous neurotransmitters and
feedback systems (Figs 4 and 5). These mechanisms are
mainly protective in nature. The mechanisms involved in centrally mediated pain transmission are demonstrated in


Figure 5. In general, as tissue heals the physiological

changes ensuing from inflammatory pain resolve.
The progression from acute inflammatory pain to chronic
neuropathic pain is poorly understood. There are three
mechanisms that are central to the mediation of chronic
neuropathic pain. First is the peripheral component with
release of multiple inflammatory mediators responsible for
the so-called positive symptoms, including hypersensitivity,
allodynia, and erythema. Second is the central component,
through the wind-up mechanism, that is mediated through
the dorsal horn neurones and involves several areas of the
CNS.94 Third is the concept of central plasticity, in which
both an excess of excitatory transmission and a loss of inhibitory transmission lead to an unfettered barrage of CNS input
from the dorsal horn of the spinal cord.95 Despite this highly
simplified model, the pathophysiology of neuropathic pain
remains poorly understood,96 and multiple mechanisms
remain to be elucidated.
The concept of pre-emptive analgesia focuses primarily on
the early timing of analgesic therapy, whereas preventive analgesia focuses primarily on timing, duration, and efficacy of
analgesic therapy.97 A significant body of literature supporting pre-emptive analgesia has been withdrawn, thus creating
ambiguity about the efficacy of this technique. The preventive model of analgesia has demonstrated clinical benefit,98
and is the basis for the multimodal technique. The multimodal technique preserves total body nitrogen and
enhances postoperative recovery and rehabilitation.99 100

Multimodal approach to pain management

Opioids still remain the mainstay of perioperative pain management (Fig. 6). While their judicious use offers analgesia
through central and peripheral mechanisms, they are
associated with many side-effects including an increased incidence of PONV, sedation, drowsiness, and pruritus, which
delay discharge and add cost to postoperative care.101 102
Additionally, there are animal data that demonstrate potentiation by opioids of tumour growth and tumour angiogenesis.103 It is believed that this is regulated through the
m-opioid receptor.104 A corollary for this concept has been
drawn in breast and prostate cancer studies in two retrospective studies. When regional anaesthesia was used instead of
postoperative opioid analgesia, the recurrence rate and metastases for breast cancer were lower, and the risk of prostate
cancer recurrence was similarly decreased.105 106
NSAIDs, including COX-2 inhibitors, provide opioid-sparing
(reduced opioid dosing requirements) and reduce some
opioid-related side-effects.52 107 Where bleeding is a
concern for the surgical procedure (e.g. tonsillectomies),
the use of non-selective NSAIDs should be avoided.25 108 A
meta-analysis suggested that the safety profile of selective
COX-2 inhibitors in this setting can be useful.109 After the
withdrawal of several COX-2 products due to their long-term
cardiovascular risks, their use in the acute postoperative
setting was also called into question. An editorial suggests
that there still clearly remains immediate and intermediate

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still of paramount importance to minimize acute postoperative pain and progression to chronic pain.
Many patients who present for surgical procedures do so
because of pain, and preoperative pain is a known risk
factor for postoperative pain.69 Therefore, a thorough preoperative assessment is essential. As alluded to previously,
certain surgeries, namely Caesarean section, coronary
artery bypass grafting, inguinal hernia repair, breast
surgery, thoracotomy, and amputation, have a higher incidence of progression to chronic pain.72 81
Preoperative anxiety has been correlated with increased
postoperative pain.82 83 Despite this, the effect of preoperative
benzodiazepine therapy on postoperative pain is unclear.84 85
However, the incidence of side-effects from administration of
benzodiazepines is low. Preoperative lorazepam results in
reduced pain after abdominal hysterectomy,86 and patients
self-reported improvement in at least one other study with administration of preoperative midazolam.87
There have been several studies on genetic factors predisposing to both acute postoperative pain and its progression
to chronic pain.88 These are small studies without sufficient
data to allow for individual patient stratification in the clinical
Opioid tolerance stemming from long-term chronic opioid
use is an important risk factor for increasing the complexity
of treating postoperative acute pain. Thus, a quantification of
opioid use in addition to bioavailability is important in the
perioperative setting. Opioid management in these patients
remains controversial; however, multimodal analgesia has
been used successfully.89
Females require more analgesics90 and are also more susceptible to developing chronic pain.83 Several of the surgeries
above are more common in women, and multimodal analgesia has been demonstrated to reduce the progression to
chronic pain in these patients.91 92

Chandrakantan and Glass


Multimodal therapies for PONV and pain



coupling between
synaptic activity
and perfusion


IL-1, IL-6



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during peak














Pre-synaptic nerve ending

Post-synaptic nerve ending

Fig 4 Microglia and inflammation. With permission from Maletic and colleagues (2009).147

benefit from COX-2 inhibition given for short durations such

as postoperative pain, although long-term benefit remains
unclear.110 There is no increased cardiovascular risk in
patients receiving short-term selective COX-2 inhibitors
after non-cardiac surgery.111 In one major study, when oral
ibuprofen (non-selective NSAID) was compared with celecoxib (COX-2 inhibitor), they were both similarly efficacious
in reduction of postoperative pain, constipation, and early

need for rescue analgesia.112 Thus, where bleeding is of

minimal risk, non-selective NSAIDs are most appropriate,
but where bleeding is a concern, a COX-2 inhibitor should
be used.
Ketamine, because of its unique mode of action, has been
studied extensively, especially in the orthopaedic literature.
Small doses (0.15 mg kg21 i.v.) improve recovery after outpatient arthroscopy.113 In a large analysis, ketamine was



Chandrakantan and Glass

Dorsal horn neuron

Central terminal of
primary sensory neutron

Trk B














Fig 5 Mechanisms of central pain transmission. Reproduced from Costigan and Woolf (2000)148 with permission from Elsevier.

intervention along
pain pathways

Opioids, APAP,
Clonidine, Ketamine,
Gabapentin, Tricyclics

5. Perception

6. CNS responses
Muscle relaxants,
Beta blockers
1. Transduction

4. Modulation

NSAIDS, COX-2 Inhibitors,

Anti-Histamines, Topical
local anesthetics

Opioids, Clonidine
APAP, COX-2 Inhibitors,
Ketamine Gabapentin

2. Conduction
Peripheral nerve block
local anesthetics

3. Transmission
Epidural block
local anesthetics

Fig 6 Multimodal approach to pain management. With permission from Raymond Sinatra, MD.


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Sub P

Multimodal therapies for PONV and pain

Regional anaesthesia, whether neuraxial, via a peripheral

nerve block, or both, is an important component of a multimodal regimen. When using regional anaesthesia, it is not
only the modality, but also the duration of therapy that is important. Local anaesthetic administration into the wound has
been studied as part of multimodal regimens in laparoscopic
surgeries. Although there are benefits in the immediate postoperative period (up to 4 h), these differences are less pronounced over time.130 131 The results from single-shot
peripheral nerve block studies also substantiate this effect,
with early postoperative pain relief, but a high percentage
of patients require adjuvant pain therapy at 24 h and up to
7 days.132 When continuous perineural catheters (from 2 to
7 days) were used in combination with NSAIDs, postoperative
analgesia beyond 24 h was very good.133 Clonidine, when
added as part of a single-shot upper extremity nerve block,
enhances the duration of action of the block.134
In a meta-analysis, the use of regional anaesthesia
decreased all-cause mortality and multiple morbidity
indices.135 Therefore, the use of neuraxial anaesthesia
when appropriate might have several effects independent
of pain control. Epidural anaesthesia (continued after operation) combined with general anaesthesia was superior to
general anaesthesia alone in multiple outcomes.136 There
are also data to indicate that in thoracotomy surgeries,
which are at high risk for chronic pain, the use of perioperative epidural analgesia decreases the incidence of chronic
pain.137 Neuraxial analgesia is not beneficial in reducing
the progression to chronic pain for all high-risk surgeries;
however, the studies are small and further data are
needed.138 Spinal anaesthesia compared with general anaesthesia for hysterectomy decreased the incidence of
chronic pain in one retrospective analysis.139 Nitrous oxide
has also been suggested to reduce the incidence of progression to chronic pain; however, further study is needed.140
There is value to using several pharmacological agents as
part of a neuraxial block. The addition of clonidine to a bupivacaine/fentanyl solution significantly reduced pain, but
side-effects were noted to be dose-dependent for increasing
clonidine.141 Concerns over hypotension have limited use of
clonidine in the obstetric population. However, at least one
study did not demonstrate adverse sequelae due to this.142
The optimal combination of bupivacaine, fentanyl, clonidine,
and infusion rate has been determined. The combination
that provided the greatest pain relief at the lowest infusion
rate was 9 mg h21 bupivacaine, 21 mg h21 fentanyl, and 5
mg h21 clonidine infused at 7 ml h21.143
Postoperative pain can also be reduced by nonpharmacological adjuvants. Transcutaneous electrical nerve
stimulation (TENS), when used at sub-noxious frequency
over the wound area, reduces postoperative analgesic consumption.144 Peri- and postoperative wound cooling significantly reduces postoperative analgesic consumption
without an increase in wound infections.145 Studies have
suggested a role of heat in peripheral sensitization.146
However, further studies are needed for all of the above modalities before definitive conclusions can be drawn.


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opioid-sparing with a low incidence of side-effects.55 When

i.v. ketamine was added into a multimodal regimen that
included postoperative epidural analgesia, the progression
to chronic pain was reduced.114 Also, ketamine added to
an epidural multimodal regimen improved analgesia, demonstrating that its efficacy is not confined to the i.v. route
alone.115 The effects of oral ketamine on chronic pain are
complex, and there are varying degrees of efficacy depending on the type of chronic pain.116 Early administration of
ketamine seems important in the prevention of
chronic pain. Dextromethorphan is another N-methylD-aspartate-type
glutamate receptor antagonist that
prevents central wind up and has other antinociceptive
mechanisms of action. Despite a fair number of studies on
its use, the results remain conflicting.101
Gabapentin has been studied in multiple small trials that
have been analysed in several large meta-analyses. Despite
demonstrating opioid-sparing effects, superior acute postoperative analgesia, and a decrease in pain scores, a decrease
in opioid-related side-effects was not noted.117 118 The most
favourable data with the fewest side-effects came from a
single dose of 1200 mg of gabapentin given in the preoperative
setting.119 These effects have only been shown in the acute
postoperative setting; gabapentin has not been shown to decrease the progression to chronic pain.120 121 Pregabalin was
evaluated as part of a multimodal regimen for total knee
arthroplasty surgery, and was continued for 14 days into the
postoperative period. There was a statistically significant reduction in chronic pain at 6 months; however, there was immediate peri- and postoperative confusion- and sedation-related
issues that were attributed to dosing.122 Similar to COX-2 inhibitors, several retracted articles on pregabalin bring its routine
use into question as part of a multimodal regimen, and thus
more studies are warranted. One might expect its actions to
be similar to gabapentin. The antidepressant venlafaxine,
when given before operation/perioperatively, reduced progression to post-mastectomy pain; however, the study did
not use a multimodal analgesic regimen.123 Therefore, more
studies are needed with antidepressants before definitive conclusions can be made as to their role in preventive analgesia.
Two of the a-2 agonists have been studied as part of the
multimodal regimen: dexmedetomidine and clonidine. Dexmedetomidine has shown to reduce opioid-related sideeffects, enhance analgesia, and was devoid of side-effects
when used for acute postoperative pain control as part of
an i.v. patient-controlled analgesia regime.124 When used
for postoperative analgesia and recovery, dexmedetomidine
plus morphine compared with morphine alone demonstrated
an additive effect.125 Dexmedetomidine as part of a perioperative analgesic regimen decreases opioid requirements,
PONV, and postoperative stay.126 I.V. clonidine, on the
other hand, has not demonstrated any efficacy in the treatment of postoperative pain.127 128 However, when used via
the neuraxial route, clonidine as part of a multimodal
regime is effective in reducing both acute postoperative
pain and progression to chronic pain.129




A planned multimodal approach to pain management can
significantly reduce acute postoperative pain and its progression to chronic pain. Blockade of both peripheral and central
sensitization through the use of multiple agents and
approaches is critical. The number of agents is important;
however, the duration of therapy is also critical to ensure
that analgesia is continued into the postoperative period to
ensure mobilization and recovery. While there are data to
support several individual agents and modalities in reducing
progression to chronic pain, further study is needed to delineate the exact risk factors and optimal drug combinations in
preventing chronic pain.

Conflict of interest
None declared.

The authors have no external sources of funding related to
this article.








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